scholarly journals The ability of TRIM3 to induce growth arrest depends on RING-dependent E3 ligase activity

2014 ◽  
Vol 458 (3) ◽  
pp. 537-545 ◽  
Author(s):  
Radhika Raheja ◽  
Yuhui Liu ◽  
Ellen Hukkelhoven ◽  
Nancy Yeh ◽  
Andrew Koff
Keyword(s):  
Growth Arrest ◽  
E3 Ligase ◽  
Growth Suppression ◽  
Tumour Suppressor ◽  
Bona Fide ◽  
Induce Growth Arrest

The present study demonstrates that growth suppression by TRIM3, a bona fide tumour suppressor, is RING-dependent and associated with its E3 ligase activity.

A Critical Role for the Bcl-2 Pathway in Notch-Mediated B Cell Apoptosis, Where Growth Arrest Is Independent of the E2A, IL-3 and p21Waf1/p27Kip1 Pathways.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 237-237 ◽  
Author(s):  
Patrick A. Zweidler-McKay ◽  
Julian J. Lum ◽  
Craig B. Thompson ◽  
Warren S. Pear
Keyword(s):  
Cell Cycle ◽  
B Cell ◽  
Notch Signaling ◽  
Cell Apoptosis ◽  
Therapeutic Approach ◽  
Critical Role ◽  
Growth Arrest ◽  
Model System ◽  
B Cell Malignancies ◽  
Induce Growth Arrest

Abstract The Notch receptor pathway regulates critical cell fate decisions in multiple developmental systems, including hematopoiesis. We have previously demonstrated that Notch signaling induces growth arrest and apoptosis in a wide range of human B cell malignancies and has potential as a B cell-specific therapeutic approach. In order to identify the mechanisms of growth arrest and apoptosis we analyzed an immortalized murine progenitor B cell line derived from Bax/Bak double knockout mice. These cells are unable to undergo apoptosis since they lack the pro-apoptotic effectors of the Bcl-2 pathway, and have been shown to be resistant to multiple apoptotic stimuli. Here we report that induction of Notch signaling through expression of several family members (Notch1, Notch4, Hes1) leads to rapid growth arrest, but not apoptosis, within 48 hours in these Bax-/Bak- progenitor B cells. These findings provide the first evidence for a critical role of the Bcl-2 pathway in Notch-mediated B cell apoptosis, and establish a mitochondrial-dependent mechanism for this effect. Importantly, the kinetics of growth arrest are accelerated with the expression of the Notch downstream target Hes1 as compared to the Notch receptors 1 and 4. These results extend our observation that Hes1 is sufficient to reproduce Notch-mediated B cell death, by demonstrating that Hes1 is more proximal to the critical growth inhibiting events, and may therefore provide a therapeutic target. In this model system we can isolate growth arrest from the effects on the apoptotic cascade. This provides a unique opportunity to explore the mechanism of Notch-mediated growth arrest. Prior studies have suggested that Notch signaling may induce growth arrest through inhibition of the E2A pathway, or through upregulation of the cell cycle regulators p21Waf1 and p27Kip1. In this model system, inhibition of the E2A pathway is not sufficient to induce growth arrest. Similarly, Hes1 does not upregulate either p21Waf1 or p27Kip1, suggesting that this is not the mechanism of growth arrest. To explore whether Notch/Hes1 induce growth arrest through inhibition of the IL-3 pathway, we compared phenotypic and functional aspects of Hes1 expression and IL-3 withdrawal. Although the timing and phenotypic effects (cell size, cell cycle and metabolic studies) were quite similar, Hes1 growth arrested cells lose their ability to migrate in response to the pan-B chemo-attractant SDF1a compared to IL-3 withdrawn cells. In summary, these results demonstrate that Notch/Hes1-mediated B cell apoptosis relies critically on pro-apoptotic members of the Bcl-2 pathway, Bax/Bak. Furthermore, growth arrest when isolated from apoptosis does not rely on inhibition of the E2A or IL-3 pathways, nor upregulation of p21Waf1/ p27Kip1. These findings provide the first insight into the mechanisms of Notch/Hes1-mediated B cell growth arrest and apoptosis and will help guide the development of Notch/Hes1 signaling as a cell-type specific therapeutic approach for B cell malignancies.

scholarly journals Growth Suppression by an E2F-Binding-Defective Retinoblastoma Protein (RB): Contribution from the RB C Pocket

1998 ◽  
Vol 18 (7) ◽  
pp. 4032-4042 ◽  
Author(s):  
Laura L. Whitaker ◽  
Heyun Su ◽  
Rajasekaran Baskaran ◽  
Erik S. Knudsen ◽  
Jean Y. J. Wang
Keyword(s):  
Cell Growth ◽  
Tyrosine Kinase ◽  
Protein Binding ◽  
Growth Arrest ◽  
Retinoblastoma Protein ◽  
Growth Suppression ◽  
Peptide Motif ◽  
Abl Tyrosine Kinase ◽  
Transcription Regulators

ABSTRACT Growth suppression by the retinoblastoma protein (RB) is dependent on its ability to form complexes with transcription regulators. At least three distinct protein-binding activities have been identified in RB: the large A/B pocket binds E2F, the A/B pocket binds the LXCXE peptide motif, and the C pocket binds the nuclear c-Abl tyrosine kinase. Substitution of Trp for Arg 661 in the B region of RB (mutant 661) inactivates both E2F and LXCXE binding. The tumor suppression function of mutant 661 is not abolished, because this allele predisposes its carriers to retinoblastoma development with a low penetrance. In cell-based assays, 661 is shown to inhibit G1/S progression. This low-penetrance mutant also induces terminal growth arrest with reduced but detectable activity. We have constructed mutations that disrupt C pocket activity. When overproduced, the RB C-terminal fragment did not induce terminal growth arrest but could inhibit G1/S progression, and this activity was abolished by the C-pocket mutations. In full-length RB, the C-pocket mutations reduced but did not abolish RB function. Interestingly, combination of the C-pocket and 661 mutations completely abolished RB’s ability to cause an increase in the percentage of cells in G1 and to induce terminal growth arrest. These results suggest that the A/B or C region can induce a prolongation of G1 through mechanisms that are independent of each other. In contrast, long-term growth arrest requires combined activities from both regions of RB. In addition, E2F and LXCXE binding are not the only mechanisms through which RB inhibits cell growth. The C pocket also contributes to RB-mediated growth suppression.

scholarly journals DNA Damage Regulates UHRF1 Stability via the SCFβ-TrCPE3 Ligase

2013 ◽  
Vol 33 (6) ◽  
pp. 1139-1148 ◽  
Author(s):  
Hao Chen ◽  
Honghui Ma ◽  
Hiroyuki Inuzuka ◽  
Jianbo Diao ◽  
Fei Lan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Damage ◽  
Tumor Recurrence ◽  
Ring Finger ◽  
E3 Ligase ◽  
Casein Kinase 1 ◽  
N Terminus ◽  
Steady State Levels ◽  
Bona Fide ◽  
Methylation Patterns

UHRF1 (ubiquitin-like, with PHD and RING finger domains 1) is a critical epigenetic player involved in the maintenance of DNA methylation patterns during DNA replication. Dysregulation of the UHRF1 level is implicated in cancer onset, metastasis, and tumor recurrence. Previous studies demonstrated that UHRF1 can be stabilized through USP7-mediated deubiquitylation, but the mechanism through which UHRF1 is ubiquitylated is still unknown. Here we show that proteasomal degradation of UHRF1 is mediated by the SCFβ-TrCPE3 ligase. Through bioinformatic and mutagenesis studies, we identified a functional DSG degron in the UHRF1 N terminus that is necessary for UHRF1 stability regulation. We further show that UHRF1 physically interacts with β-TrCP1 in a manner dependent on phosphorylation of serine 108 (S108UHRF1) within the DSG degron. Furthermore, we demonstrate that S108UHRF1phosphorylation is catalyzed by casein kinase 1 delta (CK1δ) and is important for the recognition of UHRF1 by SCFβ-TrCP. Importantly, we demonstrate that UHRF1 degradation is accelerated in response to DNA damage, coincident with enhanced S108UHRF1phosphorylation. Taken together, our data identify SCFβ-TrCPas a bona fide UHRF1 E3 ligase important for regulating UHRF1 steady-state levels both under normal conditions and in response to DNA damage.

Role of ESCRT component HD-PTP/PTPN23 in cancer

2017 ◽  
Vol 45 (3) ◽  
pp. 845-854 ◽  
Author(s):  
Marie-Claude Gingras ◽  
Jalal M. Kazan ◽  
Arnim Pause
Keyword(s):  
Plasma Membrane ◽  
Cancer Susceptibility ◽  
Tumour Suppressor ◽  
Tumour Suppressor Genes ◽  
Surface Receptors ◽  
Endosomal Sorting ◽  
Bona Fide

Sustained cellular signalling originated from the receptors located at the plasma membrane is widely associated with cancer susceptibility. Endosomal sorting and degradation of the cell surface receptors is therefore crucial to preventing chronic downstream signalling and tumorigenesis. Since the Endosomal Sorting Complexes Required for Transport (ESCRT) controls these processes, ESCRT components were proposed to act as tumour suppressor genes. However, the bona fide role of ESCRT components in tumorigenesis has not been clearly demonstrated. The ESCRT member HD-PTP/PTPN23 was recently identified as a novel haplo-insufficient tumour suppressor in vitro and in vivo, in mice and humans. In this mini-review, we outline the role of the ESCRT components in cancer and summarize the functions of HD-PTP/PTPN23 in tumorigenesis.

PPAR ? activators induce growth arrest and process extension in B12 oligodendrocyte-like cells and terminal differentiation of cultured oligodendrocytes

2003 ◽  
Vol 72 (4) ◽  
pp. 425-435 ◽  
Author(s):  
Alejandro D. Roth ◽  
Andrea V. Leisewitz ◽  
Juan E. Jung ◽  
Patricia Cassina ◽  
Luis Barbeito ◽  
...  
Keyword(s):  
Growth Arrest ◽  
Terminal Differentiation ◽  
Induce Growth Arrest
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